MAPK phosphatases (MKPs) are the largest class of phosphatases involved in down-regulating Mitogen-activated protein kinases (MAPK) signaling. [1] [2] MAPK signalling pathways regulate multiple features of development and homeostasis. [3] [4] This can involve gene regulation, cell proliferation, programmed cell death and stress responses. [5] MAPK phosphatases are therefore important regulator components of these pathways.
MAPK phosphatases are only found in eukaryotes and negatively regulate MAP kinases to act as negative feedback. [5] MKPs are also known as dual-specificity phosphatases (DUSPs) [6] because they deactivate MAPK by dephosphorylating the Threonine and the Tyrosine residues residing in MAPKs activation site. [7] MKPs have a catalytic region at their C-terminus and a regulatory region at their N-terminus. [8] The position where the MAPK binds to MKP is found near the N-terminus of MKP. The binding is due to the electrostatic interactions of the positively charged residues on the MKP binding portion with the negatively charged residues on the MAPK binding site. [9]
There are 10 [10] main MKPs that can be further broken down into three sub-classes which are representative of either their genomic structure or the type of substrate (MAPK) they bind to. [11] These include DUSP1, DUSP2, DUSP4 and DUSP5 that belong to subgroup 1. DUSP6, DUSP7, DUSP9 and DUSP10 belong to subgroup 2. DUSP8 and DUSP16 belong to subgroup 3, these subgroups are based on the genomic structure of the MKPs. [12] The newest MKP-8 brings the total MKPs to 11, MKP-8 plays a role in inhibiting p38 kinase. [13]
Dual specificity phosphatases (DUSPs) also belong to the family of protein thyrosine phosphatases. [14] MKPs are grouped into type I, II and III; in which type I MKPs are located in the nuclear region, type II are located in the cytoplasmic region and type III are located in both the nuclear and cytoplasmic region. [15] The different locations of these three types of MKPs allow for them to cause different types of signaling. For example, MKP-1 (a type I MKP) controls gene expression by inactivating the subcellular group of MAPKs. [16] Note that without the LXXLL motif (GFP-MKP-147-367) the MKP-1 cannot localize inside the nucleus and it comes before the CH2A domain. [17] The newest MKP, MKP-8, belongs to group I because it is located in the nuclear region of the cell [18] A recent study shows that histone deacetylase isoforms (HDAC1, -2, and -3) deacetylate MKP-1 and that this post-translational modification increases MAPK signaling and innate immune signaling. [19]
Although the N-terminal region is the quite distinct between each MKP, they all normally contain CH2 domains. [20] In MKP-1, MAPK binds to the active site that is between the CH2A and CHB domains located in the N-terminal. [21] [22]
An example of a type II MKP is MKP-3 which, regulates the activity of ERK2 by deposphorylating it and holding it in the cytoplasmic region. [23] MKP-3 also binds to ERK2 regardless of whether it is phosphorylated or not. [24] MKP-4 is another MKP that belongs to Type I and, is distinct from other MKPs in this subgroup because it is only found in placenta, kidney and embryonic liver cells. [25] MKP-5 is a type III MKP that binds specifically to p38 and SPK/JNK and is found both in the cytoplasmic and nuclear regions of a cell. [26] MKP-5 is only located in the heart, lung, liver, kidney and skeletal muscle cells. [27] There are also MKPs that belong to a group called Atypical MKPs. For example, Vaccina H1-related (VHR) is an atypical MKP because it only has the DUSP region. [28] VHR is only found in lymphoid and hematopoietic cells, and it inactivates the ERK1/2 and JNKs in T-cell receptors. [29] VHR also induces cell cycle arrest. [30] [31]
| Name | Alt. name | Sub Group |
|---|---|---|
| DUSP1 | MKP-1 | I |
| DUSP2 | I | |
| DUSP4 | MKP-2 | I |
| DUSP5 | I | |
| DUSP6 | MKP-3 | II |
| DUSP7 | II | |
| DUSP8 | III | |
| DUSP9 | MKP-4 | II |
| DUSP10 | MKP-5 | ? |
| DUSP14 | MKP-6 | ? |
| DUSP16 | MKP-7 | III |
| DUSP26 | MKP-8 | I |
A mitogen-activated protein kinase is a type of protein kinase that is specific to the amino acids serine and threonine. MAPKs are involved in directing cellular responses to a diverse array of stimuli, such as mitogens, osmotic stress, heat shock and proinflammatory cytokines. They regulate cell functions including proliferation, gene expression, differentiation, mitosis, cell survival, and apoptosis.
In molecular biology, extracellular signal-regulated kinases (ERKs) or classical MAP kinases are widely expressed protein kinase intracellular signalling molecules that are involved in functions including the regulation of meiosis, mitosis, and postmitotic functions in differentiated cells. Many different stimuli, including growth factors, cytokines, virus infection, ligands for heterotrimeric G protein-coupled receptors, transforming agents, and carcinogens, activate the ERK pathway.
Mitogen-activated protein kinase 1, also known as ERK2, is an enzyme that in humans is encoded by the MAPK1 gene.
Mitogen-activated protein kinase 14, also called p38-α, is an enzyme that in humans is encoded by the MAPK14 gene.
Mitogen-activated protein kinase 3, also known as p44MAPK and ERK1, is an enzyme that in humans is encoded by the MAPK3 gene.
Mitogen-activated protein kinase 8 is a ubiquitous enzyme that in humans is encoded by the MAPK8 gene.
Dual specificity protein phosphatase 1 is an enzyme that in humans is encoded by the DUSP1 gene.
Dual specificity mitogen-activated protein kinase kinase 6 also known as MAP kinase kinase 6 or MAPK/ERK kinase 6 is an enzyme that in humans is encoded by the MAP2K6 gene, on chromosome 17.
Dual specificity mitogen-activated protein kinase kinase 7, also known as MAP kinase kinase 7 or MKK7, is an enzyme that in humans is encoded by the MAP2K7 gene. This protein is a member of the mitogen-activated protein kinase kinase family. The MKK7 protein exists as six different isoforms with three possible N-termini and two possible C-termini.
Dual specificity phosphatase 6 (DUSP6) is an enzyme that in humans is encoded by the DUSP6 gene.
Dual specificity protein phosphatase 3 is an enzyme that in humans is encoded by the DUSP3 gene.
Dual specificity protein phosphatase 4 is an enzyme that in humans is encoded by the DUSP4 gene.
Dual specificity protein phosphatase 10 is an enzyme that in humans is encoded by the DUSP10 gene.
Dual specificity protein phosphatase 2 is an enzyme that in humans is encoded by the DUSP2 gene.
Dual specificity protein phosphatase 7 is an enzyme that in humans is encoded by the DUSP7 gene.
Dual specificity protein phosphatase 16 is an enzyme that in humans is encoded by the DUSP16 gene.
Dual specificity protein phosphatase 5 is an enzyme that in humans is encoded by the DUSP5 gene.
Mitogen-activated protein kinase 11 is an enzyme that in humans is encoded by the MAPK11 gene.
Dual-specificity phosphatase is a form of phosphatase that can act upon tyrosine or serine/threonine residues.
Candidalysin is a cytolytic 31-amino acid α-helical amphipathic peptide toxin secreted by the opportunistic pathogen Candida albicans. This toxin is a fungal example of a classical virulence factor. Hyphal morphogenesis in C. albicans is associated with damage to host epithelial cells; during this process Candidalysin is released and intercalates in host membranes. Candidalysin promotes damage of oral epithelial cells and induces lactate dehydrogenase release and calcium ion influx. It is unique in the fact that it is the first peptide toxin to be identified in any human fungal pathogen.